Neurotoxic secretory products from mononuclear phagocytes (MP; perivascular macrophages and microglia) play a pivotal role in the neuropathogenesis of HIV-1-associated dementia (HAD). Thus, we posit that the proteome of virus-infected and immune activated macrophages could be harnessed to unravel potential molecular markers or fingerprints of disease. Such markers, when combined with other disease associated proteins, could predict the onset, progression and response to therapy for HAD. All together the lack of biomarkers as predictors of cognitive dysfunction in HIV-1 infection is timely and significant for gauging treatment responses. Our goal is to use this infrastructure to develop a "new" series of biomarkers found in laboratory assays and reflective of HIV-1 infection and immune activation as it occurs in the human host. We will then test the hypothesis that serum and cerebrospinal fluid (CSF) will contain a spectrum of MP activation markers (or fingerprints) that can predict HAD. The strengths of this proposal lies in its technical innovation, its approach, the interdisciplinary group of investigators, the strong research environment and a proven successful track record in proteomics. Aim 1. To identify the secretome (profile of secreted proteins) of HIV-1 infected and immune competent human monocyte-derived macrophages (MDM). The work in this aim reflects the hypothesis that markers of HIV-1 associated dementia (HAD) derive, in significant measure, from products of brain mononuclear phagocyte (MP; perivascular macrophage and microglial) activation and viral infection. Aim 2. To determine protein fingerprints (proteome profiles) of serum and CSF of HIV-1 infected patients with or at risk for cognitive impairment. The long-term goal of this aim is to uncover biomarkers specific for HAD and to see if they are based on products of immune competent virus-infected MDM as demonstrated in aim 1.